Population genetic analysis of natural populations has been used to study the genetic health and disease susceptibility of several species. In addition, new methodologies (particularly reverse fragment length polymorphism, mitochondrial DNA and genetic fingerprinting) have been applied to populations of known background to interpret their behavior under different historic scenarios. The African cheetah has been shown to be a genetically depauperate relative to other species based upon a wide variety of methods: allozyme variants, two dimensional gel electrophoresis, allogeneic skin grafts, morphological asymmetry and DNA variants using mitochondrial DNA, major histocompatibility complex (MHC) class I cDNA, and feline-specific hypervariable probes. Apparent physiological consequences of historic inbreeding depression are observed in reproductive norms and in a relatively high degree of infant mortality which has been decreased by subspecies hybridization. DNA variation using nuclear genes (MHC class I copies) and mitochondrial DNA variation was used to study genetic changes in free-ranging populations of pumas, whales, jackals, foxes, and orangutans. Appreciable sensitivity of these methods for detecting perturbations in population genetic structure was achieved. Procedures of molecular systematics were applied to developing phylogeny of marsupial families as well as feline groups. Molecular topologies for these groups hold much promise in reconstructing evolutionary relationships between species and in using these relationships to interpret adaptive rearrangements in the evolution of the mammalian genome.